Currently, there is growing evidence indicating that a functional imbalance between Th1 (pathogenic) and Th2 (regulatory) T helper cell subsets is a key factor in the pathogenesis of T cell mediated autoimmune diseases such as insulin dependent diabetes mellitus, multiple sclerosis and rheumatoid arthritis. As a result, one approach to immunotherapy is to promote 'immune deviation' as a means to induce antigen-specific regulatory Th2 cells to suppress the activity of the relevant autoreactive Th1 cells. We and others have shown that this approach is indeed effective in various animal models of T cell mediated autoimmunity. The current challenge, however, is to establish methods of immune deviation which can effectively induce and establish long term protection in a safe manner and in turn be directly applicable to a clinical setting. Recently, DNA vaccination has proven to be a highly successful method to establish protective immunity to a plasmid DNA encoded antigen. The immunity that is induced is maintained over long periods of time and there is no detectable response to the DNA itself. The approach is highly flexible in that virtually any antigen can be expressed in vivo and there is no limit in the number of plasmid DNAs that can be injected at any one time. Therefore, DNA vaccination provides several advantages that make this method a potentially effective and novel means of immunotherapy. Using the nonobese diabetic mouse, a spontaneous murine model for insulin dependent diabetes mellitus, we will test whether plasmid DNAs encoding beta cell autoantigens and appropriate cytokines can under a number of conditions: i) effectively induce regulatory antigen-specific Th2 cells, and ii) prevent and/or treat the diabetogenic response. In this way, we will be able to determine the feasibility of DNA vaccination as a general approach to treat T cell mediated autoimmunity.